Active substance-containing adhesive patches have already been introduced on the market under the special designation transdermal therapeutic systems (TTS) and have been used in the therapy of a number of diseases.
Many of the active substances that are particulary suited for transdermal therapy are already perceptibly volatile at room temperature, or at least at the usual processing temperatures of 60 to 80.degree. C. This is disturbing since, due to the hardly foreseeable degree of active substance loss during the process in each individual case, it is not possible to achieve a safe dosage of the pharmaceutic agent. Volatility, as understood by the instant invention, is present in any case if from a shallow vessel which is filled with an excess of the pure substance covering the base of the vessel, at 100.degree. C. at least 0.1 mg substance per hour is continuously released to the environment per 10 cm.sup.2 of free surface. In particular cases, as with highly effective pharmaceutic agents, which in TTS are typically dosed at surface concentrations of around 1 mg per 10 cm.sup.2, or less, even slight volatility can be disturbing. For this reason the above definition can only serve as a rough guideline.
The problem of volatility also concerns readily volatile ingredients in TTS which have no therapeutic effect themselves but which have the function of increasing the active substance flow through the skin. Substances suitable for this purpose are for example: benzyl alcohol, butanol and other short-chain alcohols, triglycerides, high-boiling aliphatic hydrocarbons, glycerin, glycerin monooleate, isopropyl myristate or other short-chain esters, menthol or other volatile terpene derivatives (which are mixture components of a great number of natural essential oils), octanol-1 and other volatile medium-chain alcohols (e.g. oleyl alcohol), octanoic acid and other medium-chain aliphatic carboxylic acids, and many other substances.
This problem with regard to manufacturing technology, which is common to all volatile active substances and auxiliary substances (described in summary as "readily volatile ingredients" in the following) has lead to a plurality of proposals of--mostly rather complicated--constructions for TTS containing such additives. For example, a rather large quantity of ethanol is stored along with the active substance (which in this case is non-volatile) in a bag-type reservoir; during use the auxiliary substance as well as the active substance pass through a control membrane (U.S. Pat. No. 4,379,454).
Since for the user a thin, flexible construction is important, it was desirable to realize the addition of readily volatile additives in more simple adhesive patches as well--in the ideal case consisting only of a self-adhesive matrix layer and a non-adhesive backing layer. This has indeed been frequently suggested. DE-OS 42 10 165, for example, describes simple matrix TTS with an added amount of polar and nonpolar penetration enhancers.
According to this classical technique, matrix TTS, and also such matrix TTS containing readily volatile ingredients which are to remain in the pharmaceutic product, are produced in by a method in which a solution of the adhesive is mixed in a low-boiling solvent with the active substance and the volatile ingredient, the mixture is applied in the form of a film to a base film/sheet, the volatile solvent is removed by heating (in most cases up to 50 to 80.degree. C.) and the thus-obtained product is covered with a removable protective foil. In this process, solvents suitable for dissolving the adhesive are used--i.e. such solvents as are even more readily volatile than the ingredients which have been added to the system to be retained therein--for example, methanol, ethanol or isopropanol, benzene, acetone, ethyl acetate etc.
Many of the additives mentioned in DE-OS 42 10 165, for example pinene and limonene, however, are, under these conditions, so highly volatile that it is not possible to achieve a reproducible dosage with the described single-layer system structure and the described process.
In an alternative production procedure, the hot-melt process, such as described in DE 37 43 946 for the transdermal application of nitroglycerin, such problems occur at a lesser extent since active substance and auxiliary substances are melted together in a closed system and come into contact with the ambient air only for a short time, after coating. On the other hand, a number of auxiliary agents and active substances are not suitable for this process because the auxiliary substances are not sufficiently thermoplastic, the active substances are too temperature-sensitive, or because the added amount of plasticizing but volatile auxiliary substances is too small to ensure process temperatures that are sufficiently low.
The possibility of introducing a piece of nonwoven printed with volatile active substance, e.g. nicotine, solves the problem of evaporation; however, this leads to comparatively thick active substance adhesive patches.
DE 32 31 400 makes use of the migration of active substances or adjuvants between matrix layers, in order to prevent the recrystallization of active substance and adjuvant. However, this document only describes matrix layers that have each been enriched with active substance or auxiliary substance, which matrix layers--after laminating and migration--result in a TTS exhibiting advantageous active substance flow. No mention is made therein of the use of the active substance or adjuvants themselves as solvents which can be employed at room temperature. Accordingly, the advantages of the migration process for obtaining shear-resistant TTS having volatile ingredients has not been realized in this document.
EP 0 249 475 describes a delivery system consisting of component parts which are to be joined immediately prior to use. After the combination thereof, the active substance migrates from the active substance-containing layer into the layer that is initially entirely free of active substance. This results in a desired retardation of the release. In this system no migration of the active substance has occurred at the point in time when the system is applied for therapeutic treatment. Thus, the system described in the above document does not show the advantages with regard to therapy and application technology of a system where at the time of application a migration has already occurred. The retardation of the active substance release described in the system according to EP 0 249 475 in most cases is not desired. Moreover, the system according to EP 0 249 475 is further disadvantageous in so far as it does not contain any teaching as to how to proceed with readily volatile active substances; consequently it does not describe how such substances can be dosed accurately in transdermal systems.